Method for treating atrophic age related macular degeneration

ABSTRACT

Compositions and methods for treating dry age related macular degeneration (dry AMD) by administration to an intraocular location of an anti-neovascular agent (such as bevacizumab) in either a liquid or solid polymeric vehicle (or both), such as a biodegradable hyaluronic acid or PLGA (or PLA).

BACKGROUND

The present invention is directed to compositions (i.e. drug deliverysystems) and methods for treating ocular conditions, and for preventingthe occurrence of certain ocular conditions. In particular the presentinvention is directed to pharmaceutical compositions and methods fortreating and for preventing posterior ocular conditions, for example bypreventing retinal, choroidal and/or macular neovascularizations and/orfor treating various types of macular degeneration (such as age relatedmacular degeneration), by use of a drug delivery system comprising ananti-neovascular agent.

In the industrialized world the average life expectancy is over 80 yearsof age and is increasing steadily. Unfortunately, the quality of lifefor the elderly is often dramatically decreased by the ocular conditionknown as age related macular degeneration (“ARMD” or “AMD”). AMD is theleading cause of blindness worldwide and the World Health Organizationhas estimated that about 14 million people are blind or severelyimpaired because of AMD. The affliction of AMD has great impact on thephysical and mental health of the geriatric population and theirfamilies and presents a significant public health care burden. Theseminal characteristic of AMD is progressive loss of central visionattributable to degenerative and neovascular changes in the macula, aspecialized area in the center of the retina.

There are two forms of AMD, atrophic or dry AMD and neovascular or wetAMD. Typically AMD begins as dry AMD. Dry AMD is characterized by theformation of yellow plaque like deposits called drusen in the macula,between the retinal pigment epithelium (RPE) and the underlying choroid.About 15% of dry AMD patients develop wet AMD which is characterized bychoroidal neovascularization, that is by the formation of new bloodvessels in the choroid, and vision loss.

While there is no cure for AMD there are known treatments for wet AMD(the less prevalent form of AMD), such as use of anti-neovascular agentsand photodynamic therapy (laser irradiation of the macular).Anti-neovascular agents for treatment of wet AMD include agents whichblock the action of vascular endothelial growth factor (VEGF) therebyslowing angiogenesis (formation of new blood vessels in the retina)which leads to choroidal neovascularization and loss of vision in wetAMD patients. Such “anti-VEGF” agents approved or in clinical study fortreating wet AMD include bevacizumab (Avastin), ranibizumab (Lucentis),and pegaptanib (Macugen). Bevacizumab is a full-length anti-VEGFantibody approved for use in metastatic colon cancer. Ranibizumab is ahumanized anti-VEGF monoclonal antibody fragment that inhibits allisotypes of VEGF and pegaptanib is a VEGF-neutralizing aptamer thatspecifically inhibits one isoform of VEGF (VEGF-165).

Other known anti-VEGF agents include small interfering RNA (siRNAs);corticosteroids such as anacortave acetate, triamcinolone acetonide andfluocinolone acetonide; receptor tyrosine kinase inhibitors (such asvatalanib and Ruboxistaurin [decreases protein kinase C activity]);squalamine lactate, and; growth factors, including pigmentepithelium-derived factor. siRNAs can inhibit VEGF production and VEGFreceptor production, corticosteroids can treat the DME aspect of wetAMD, receptor tyrosine kinase inhibitors inhibit downstream effects ofVEGF, and squalamine lactate inhibits plasma membrane ion channels withdownstream effects on VEGF.

An ocular condition can include a disease, aliment or condition whichaffects or involves the eye or one of the parts or regions of the eye.Broadly speaking the eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball. A front of the eye or anterior ocularcondition is a disease, ailment or condition which affects or whichinvolves an ocular region or site, such as a periocular muscle, an eyelid or an eye ball tissue or fluid which is located anterior to theposterior wall of the lens capsule or ciliary muscles. Thus, a front ofthe eye ocular condition primarily affects or involves, the conjunctiva,the cornea, the conjunctiva, the anterior chamber, the iris, theposterior chamber (behind the iris but in front of the posterior wall ofthe lens capsule), the lens and the lens capsule as well as bloodvessels, lymphatics and nerves which vascularize, maintain or innervatean anterior ocular region or site.

A front of the eye (anterior) ocular condition can include a disease,ailment or condition, such as for example, aphakia; pseudophakia;astigmatism; blepharospasm; cataract; conjunctival diseases;conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction;myopia; presbyopia; pupil disorders; refractive disorders andstrabismus. Glaucoma can be considered to be a front of the eye ocularcondition because a clinical goal of glaucoma treatment can be to reducea hypertension of aqueous fluid in the anterior chamber of the eye (i.e.reduce intraocular pressure).

A posterior (or back of the eye) ocular condition is a disease, ailmentor condition which primarily affects or involves a posterior ocularregion or site such as choroid or sclera (in a position posterior to aplane through the posterior wall of the lens capsule), vitreous,vitreous chamber, retina, optic nerve (i.e. the optic disc), and bloodvessels and nerves which vascularize or innervate a posterior ocularregion or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, macular degeneration (such asnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (such as cystoid macular edema anddiabetic macular edema); Behcet's disease, retinal disorders, diabeticretinopathy (including proliferative diabetic retinopathy); retinalarterial occlusive disease; central retinal vein occlusion; uveiticretinal disease; retinal detachment; ocular trauma which affects aposterior ocular site or location; a posterior ocular condition causedby or influenced by an ocular laser treatment; posterior ocularconditions caused by or influenced by a photodynamic therapy;photocoagulation; radiation retinopathy; epiretinal membrane disorders;branch retinal vein occlusion; anterior ischemic optic neuropathy;non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa andglaucoma. Glaucoma can also be considered a posterior ocular conditionbecause a therapeutic goal of glaucoma treatment is to prevent the lossof or reduce the occurrence of loss of vision due to damage to or lossof retinal cells or optic nerve cells (i.e. neuroprotection). As statedmacular degeneration, such as AMD is a leading cause of blindness in theworld and it is estimated that thirteen million Americans have evidenceof macular degeneration. Macular degeneration results in a break downthe macula, the light-sensitive part of the retina responsible for thesharp, direct vision needed to read or drive. Central vision isespecially affected. Macular degeneration is diagnosed as either dry(atrophic) or wet (exudative). The dry form of macular degeneration ismore common than the wet form of macular degeneration, with about 90% ofAMD patients being diagnosed with dry AMD. The wet form of the diseaseusually leads to more serious vision loss. Macular degeneration canproduce a slow or sudden painless loss of vision. The cause of maculardegeneration is not clear. The dry form of AMD may result from the agingand thinning of macular tissues, depositing of pigment in the macula, ora combination of the two processes. With wet AMD, new blood vessels growbeneath the retina and leak blood and fluid. This leakage causes retinalcells to die and creates blind spots in central vision.

Macular edema (“ME”) can result in a swelling of the macula. The edemais caused by fluid leaking from retinal blood vessels. Blood leaks outof the weak vessel walls into a very small area of the macula which isrich in cones, the nerve endings that detect color and from whichdaytime vision depends. Blurring then occurs in the middle or just tothe side of the central visual field. Visual loss can progress over aperiod of months. Retinal blood vessel obstruction, eye inflammation,and age-related macular degeneration have all been associated withmacular edema. The macula may also be affected by swelling followingcataract extraction. Symptoms of ME include blurred central vision,distorted vision, vision tinted pink and light sensitivity. Causes of MEcan include retinal vein occlusion, macular degeneration, diabeticmacular leakage, eye inflammation, idiopathic central serouschorioretinopathy, anterior or posterior uveitis, pars planitis,retinitis pigmentosa, radiation retinopathy, posterior vitreousdetachment, epiretinal membrane formation, idiopathic juxtafovealretinal telangiectasia, Nd:YAG capsulotomy or iridotomy. Some patientswith ME may have a history of use of topical epinephrine orprostaglandin analogs for glaucoma. The first line of treatment for MEis typically anti-inflammatory drops topically applied. The increase inretinal capillary permeability and subsequent retinal edema of maculaedema can ensue from of a breakdown of the blood retina barrier mediatedin part by vascular endothelial growth factor (VEGF), a 45 kDglycoprotein. It is known that VEGF can increase vascular permeability;possibly by increasing phosphorylation of tight junction proteins suchas occludin and zonula occluden. Similarly, in human non-ocular diseasestates such as ascites, VEGF has been characterized as a potent vascularpermeability factor (VPF).

Biochemically, VEGF is known to be a major contributor to the increasein the number of capillaries in tissue undergoing angiogenesis. Bovinecapillary endothelial cells will proliferate and show signs of tubestructures in vitro upon stimulation by VEGF. Upregulation of VEGF is amajor component of the physiological response to exercise and its rolein angiogenesis is suspected to be a possible treatment in vascularinjuries.

VEGF causes an intracellular signaling cascade in endothelial cells.VEGF binding to VEGF receptor-2 (VEGFR-2) initiates a tyrosine kinasesignaling cascade that stimulates the production of factors thatvariously stimulate vessel permeability (epithelial nitric oxidesynthase; (eNOS), proliferation/survival (bFGF; basic fibroblast growthfactor), migration (intercellular adhesion molecules (ICAMs); vascularcell adhesion molecules (VCAMs); matrix metalloproteases (MMPs)) andfinally differentiation into mature blood vessels. As part of theangiogenic signaling cascade, NO (nitric oxide) is widely considered tobe a major contributor to the angiogenic response because inhibition ofNO significantly reduces the effects of angiogenic growth factors.

The normal human retina contains little or no VEGF; however, hypoxiacauses upregulation of VEGF production. Disease states characterized byhypoxia-induced VEGF upregulation include, without limitation, CRVO andBRVO. This hypoxia induced upregulation of VEGF can be inhibitedpharmacologically. Pe'er J. et al., Vascular Endothelial Growth FactorUpregulation In Human Central Retinal Vein Occlusion, OPHTHALMOLOGY1998; 105:412-416. It has been demonstrated that anti-VEGF antibodiescan inhibit VEGF driven capillary endothelial cell proliferation. Thus,attenuation of the effects of VEGF introduces a rationale for treatmentof macular edema from venous occlusive disease.

Additionally, over expression of VEGF causes increased permeability inblood vessels in addition to stimulating angiogenesis. In “wet” orexudative macular degeneration, VEGF causes proliferation of capillariesinto the retina. Since the increase in angiogenesis also causes edema,blood and other retinal fluids leak into the retina causing loss ofvision. Our invention includes a novel treatment for maculardegeneration without neovascularization by use of an anti-neovascularagent, such as a VEGF inhibiting aptamer, or other VEGF-inhibitingcompound, such as a to stop the main signaling cascade for angiogenesis,thereby preventing these symptoms.

Diabetic retinopathy is the leading cause of blindness among adults aged20 to 74 years. Macular ischemia is a major cause of irreversible visionacuity loss and decreased contrast sensitivity in patients with diabeticretinopathy. The capillary nonperfusion and decreased capillary bloodflow that is responsible for this ischemia is seen clinically on thefluorescein angiogram as an increase in the foveal avascular zone (FAZ)or an irregularity of the outline of the FAZ. These findings arepredictors of the other, perhaps more well-known, sight-threateningcomplications of diabetic retinopathy, including macular edema andproliferative retinopathy. Perhaps more importantly, extensive capillarynonperfusion is also a predictor of a poor visual prognosis fromdiabetic retinopathy.

There are treatments available or in development for macular edema andproliferative retinopathy, such as laser photocoagulation, intravitrealcorticosteroids and anti-VEGF therapies. Although laser photocoagulationhas been studied for vision loss directly associated with macularischemia, there is currently no known treatment for this indication.

The exterior surface of the normal globe mammalian eye has a layer oftissue known as conjunctival epithelium, under which is a layer oftissue called Tenon's fascia (also called conjunctival stroma). Theextent of the Tenon's fascia extending backwards across the globe formsa fascial sheath known as Tenon's capsule. Under Tenon's fascia is theepisclera. Collectively, the conjunctival epithelium and the Tenon'sfascia is referred to as the conjunctiva. As noted, under Tenon's fasciais the episclera, underneath which lies the sciera, followed by thechoroid. Most of the lymphatic vessels and their associated drainagesystem, which is very efficient at removing therapeutic agents placed intheir vicinity, is present in the conjunctiva of the eye.

A therapeutic agent can be administered to the eye to treat an ocularcondition. For example the target tissue for an antihypertensivetherapeutic agent to treat the elevated intraocular pressurecharacteristic of glaucoma can be the ciliary body and/or the trabecularmeshwork. Unfortunately, administration of an ocular topicalantihypertensive pharmaceutical in the form of eye drops can result in arapid wash out of most if not all of the therapeutic agent before itreaches the ciliary body and/or the trabecular meshwork target tissue,thereby requiring frequent redosing to effectively treat a hypertensivecondition. Additionally, side effects to patients from topicaladministration of antiglaucoma medications and their preservatives rangefrom ocular discomfort to sight-threatening alterations of the ocularsurface, including conjunctival hyperemia (eye redness), stinging, pain,decreased tear production and function, decreased tear film stability,superficial punctate keratitis, squamous cell metaplasia, and changes incell morphology. These adverse effects of topical antiglaucoma eyedropscan interfere with the treatment of glaucoma by discouraging patientdosing compliance, and as well long-term treatment with eyedrops isassociated with a higher failure of filtration surgery. Asbell P. A., etal Effects of topical antiglaucoma medications on the ocular surface,Ocul Surf January 2005;3(1):27-40; Mueller M., et al. Tear film break uptime and Schirmer test after different antiglaucomatous medications,Invest Ophthalmol Vis Sci Mar. 15, 2000;41(4):S283.

It is known to administer a drug depot to the posterior (i.e. near themacula) sub-Tenon space. See eg column 4 of U.S. Pat. No. 6,413,245.Additionally, it is known to administer a polylactic implant to thesub-tenon space or to a suprachoroidal location. See eg published U.S.Pat. No. 5,264,188 and published U.S. patent application 20050244463

An anti-neovascular agent can be used for the treatment of an ocularcondition, such as a posterior ocular condition, which involvesangiogenesis such as choroidal neovascularization (“CNV”). Delivery tothe eye of a therapeutic amount of an anti-neovascular agent (a drug)can be difficult, if not impossible, for drugs with short plasmahalf-lives since the exposure of the drug to intraocular tissues islimited. Therefore, a more efficient way of delivering a drug to treat aposterior ocular condition, such as CNV, is to place the drug directlyin the eye, such as directly into the vitreous. Maurice, D. M. (1983)Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee,V. H. L. et al. (1989), Drug delivery to the posterior segment” Chapter25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby,Vol. 1, pp. 483-98; and Olsen, T. W. et al. (1995), Human scleralpermeablilty: effects of age, cryotherapy, transscleral diode laser, andsurgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.

Techniques such as intravitreal injection of a drug have shown promisingresults, but due to the short intraocular half-life of active agent,including anti-neovascular agents, intravitreal injections must befrequently repeated to maintain a therapeutic drug level. In turn, thisrepetitive process increases the potential for side effects such asinfection, retinal detachment, endophthalmitis, and cataract.

An intraocular drug delivery system can be made of a biodegradablepolymer such as a poly(lactide) (PLA) polymers,poly(lactide-co-glycolide) (PLGA) polymers, as well as copolymers of PLAand PLGA polymers. PLA and PLGA polymers degrade by hydrolysis, and thedegradation products, lactic acid and glycolic acid, are metabolizedinto carbon dioxide and water.

Drug delivery systems have been formulated with various active agents.For example, it is known to make 2-methoxyestradiol poly lactic acidpolymer implants (as rods and wafers), intended for intraocular use, bya melt extrusion method. See eg published U.S. patent application20050244471. Additionally, it is known to make brimonidine poly lacticacid polymer implants and microspheres intended for intraocular use. Seeeg published U.S. patent applications 20050244463 and 20050244506, andU.S. patent application Ser. No. 11/395,019. Furthermore, it is known tomake bimatoprost containing polylactic acid polymer implants andmicrospheres intended for intraocular use. See eg published U.S. patentapplications 2005 0244464 and 2006 0182781, and U.S. patent applicationsSer. Nos. 11/303,462, and; 11/371,118.

EP 488 401 discusses intraocular implants, made of certain polylacticacids, to be applied to the interior of the eye after a surgicaloperation for disorders of the retina/vitreous body or for glaucoma. EP430539 discusses use of a bioerodible implant which is inserted in thesuprachoroid.

U.S. application Ser. No. 11/565,917 filed Dec. 1, 2006 disclosesintraocular (including sub-tenon's) administration of various solid,drug-containing implants.

Intraocular drug delivery systems which are sutured or fixed in placeare known. Suturing or other fixation means requires sensitive oculartissues to be in contact with aspects of a drug delivery system whichare not required in order to contain a therapeutic agent within or onthe drug delivery system or to permit the therapeutic agent to bereleased in vivo. As such suturing or eye fixation means a merelyperipheral or ancillary value and their use can increase healing time,patient discomfort and the risk of infection or other complications.

U.S. patent applications Ser. Nos. 11/742,350; 11/859,310; 11/952,938;11/364,687 discuss use of intraocular compositions comprising anti-VEGFtherapeutic agent, such as bevacizumab. Formulations of macromoleculesfor intraocular use are known, See eg applications Ser. Nos. 11/370,301;11/364,687; 60/721,600; 11/116,698 and 60/567,423.

Significantly, although dry AMD is the most common form of AMD, exceptfor use of anti-oxidants (such as high dose vitamins C, E, beta caroteneand/or zinc to neutralize reactive oxygen species in the retina) “thereare no current therapies for the more common ‘dry’ AMD”. Gehrs K., etal., Age-related macular degeneration—emerging pathogenetic andtherapeutic concepts, Ann Med 2006; 38: 450-471. Thus, “there is noeffective treatment for the most prevalent atrophic (dry) form of AMD”.Petrukhin, K., New therapeutic targets in atrophic age-related maculardegeneration, Expert Opin. Ther. Targets 92007) 11(5): 625-639.

Thus it would be advantageous to have a sustained release drug deliverysystem suitable for intraocular use for treatment of dry AMD. What isneeded therefore is a composition and method for treating dry AMD.

SUMMARY

The present invention fulfills this need by providing compositions andmethods for treating dry AMD. In particular the present inventionprovides an effective intraocular therapy for treating dry AMD by use ofa sustained release drug delivery system suitable for intraocular (i.e.intravitreal) use.

Definitions

The terms below are defined to have the following meanings:

“Anti-neovascular agent” means a compound which has an anti-angiogeniceffect when administered to an eye such as by intravitreal injection orimplantation.

“Anti-VEGF agent” means a compound which inhibits an activity or aneffect of VEGF, and includes bevacizumab, ranibizumab, pegaptanib,VEGF-neutralising aptamers, anti-VEGF monoclonal antibodies, siRNAs,corticosteroids such as anacortave acetate, triamcinolone acetonide andfluocinolone acetonide; receptor tyrosine kinase inhibitors, such asvatalanib and Ruboxistaurin, squalamine lactate, and; growth factors,including pigment epithelium-derived factor.

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means ±10% of the numerical value orrange recited or claimed.

“Active agent”, “drug” and “therapeutic agent” are used interchangeablyherein and refer to any substance (including a biologic ormacromolecule) used to treat an ocular condition.

“Biocompatible” with regard to a drug delivery system means that uponintraocular administration of the drug delivery system to a mammalianeye a significant immunogenic reaction does not occur.

“Bioerodible polymer” means a polymer which degrades in vivo. Thepolymer can be a gel or hydrogel type polymer, PLA or PLGA polymer ormixtures or derivatives thereof. The words “bioerodible” and“biodegradable” are synonymous and are used interchangeably herein.

“Drug delivery system” means a liquid, gel, hydrogel, high viscosityformulation, solid implant or microspheres from which a therapeuticamount of a therapeutic agent can be released upon in vivoadministration of the drug delivery system, without any requirement thatthe drug delivery system by sutured to ocular tissue or otherwise fixedin place by an attachment means.

“Dry AMD” (also referred to as atrophic age related maculardegeneration) means a human retinal condition in which drusen arepresent in the macula but with little or no retinal neovascularization.Dry AMD includes category 1 AMD (few or only small drusen present),category 2 AMD (early AMD in which with small to moderate size drusenare present) and category 3 AMD (intermediate AMD is which numerousmedium or large drusen are present). Contrarily, “wet AMD” means a humanretinal condition characterized by the presence of retinalneovascularization (category 4 or advanced AMD) or vision loss. Smalldrusen has a diameter less than 63 microns, medium size drusen has adiameter between 63 to 124 microns, and large drusen has diameter of 125microns or more.

“Intraocular” means within or under an ocular tissue. An Intraocularadministration of a drug delivery system includes administration of thedrug delivery system to a sub-Tenon, subconjunctival, suprachoroidal,intravitreal and like locations. An intraocular administration of a drugdelivery system excludes administration of the drug delivery system to atopical, systemic, intramuscular, subcutaneous, intraperitoneal, and thelike location.

“Ocular condition” means a disease, aliment or condition which affectsor involves the eye or one or the parts or regions of the eye, such as aretinal disease. The eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

“Posterior ocular condition” means a disease, ailment or condition whichaffects or involves a posterior ocular region or site such as choroid orsclera (in a position posterior to a plane through the posterior wall ofthe lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e.the optic disc), and blood vessels and nerve which vascularize orinnervate a posterior ocular region or site.

“Substantially” means between 51% to 100% of the item or amount soqualified.

“Suitable for insertion (or implantation) in (or into) an ocular regionor site” with regard to a drug delivery system, means a drug deliverysystem which has a size (dimensions) such that it can be administered,injected, inserted or implanted without causing excessive tissue damageand without unduly physically interfering with the existing vision ofthe patient into which the implant is implanted or inserted.

“Sustained” as in “sustained period” or “sustained release” means for aperiod of time greater than three days, preferably for at least 20 days(i.e. for a period of time from 20 days to 365 days), and mostpreferably for at least 30 days. A sustained release can persist forbetween about two months and about a four months.

“Therapeutic levels” or “therapeutic amount” means an amount or aconcentration of an active agent that has been locally delivered to anocular region that is appropriate to safely treat an ocular condition soas to reduce or prevent a symptom of an ocular condition.

“Treating” means to administer a treatment to a human patient. Treatingincludes a treatment which acts to reduce an existing clinical symptom(such as the amount or extent of drusen present) of a present, diagnosedocular condition (such as dry AMD), as well as prevention ofdeterioration of (or slowing of the rate of deterioration of) thepresent, diagnosed ocular condition to another ocular condition (such aswet AMD) which has additional or new clinical symptoms (such as visionloss and/or neovascularization).

An embodiment of our invention is a method for treating a retinaldisease, such as macular degeneration, such as dry age related maculardegeneration (dry AMD). The method can comprise the step ofadministering an anti-neovascular agent to an eye of a patient with dryAMD, thereby treating the dry AMD. The anti-neovascular agent can be ananti-vascular endothelial growth factor (VEGF) agent and exemplaryanti-VEGF agent can be bevacizumab, ranibizumab and pegaptanib, as wellas derivatives, esters, salts and mixtures of these anti-VEGF agentsthereof.

Preferably, the anti-neovascular agent is administered in a methodwithin the scope of our invention as or as part of a biocompatible drugdelivery system. Thus, the biocompatible drug delivery system cancomprise the anti-neovascular agent and a polymeric vehicle associatedwith the anti-neovascular agent. The polymeric vehicle can be selectedfrom the group consisting of a polymeric lactic acid (“PLA), a polymericglycolic acid, a lactic acid-glycolic acid co-polymer (“PLGA”), apolymeric hydroxypropylmethylcellulose, and a polymeric hyaluronic acid,and mixtures thereof.

The anti-neovascular agent can be associated with the polymeric vehicleby being dispersed homogenously throughout the polymeric vehicle and theadministering step of the method can be carried out by injecting theanti-neovascular agent to an anterior intraocular location or to aposterior intraocular location, such as into the vitreous cavity.

A further embodiment of our invention is a method for treating dry AMDby preparing a biocompatible drug delivery system comprising ananti-neovascular agent (i.e. bevacizumab or a derivative, ester, or saltthereof) and a polymeric vehicle associated with the anti-neovascularagent, and injecting the drug delivery system into the vitreous cavityof the eye of a patient with dry AMD, thereby treating the dry AMD.

Preferably, a drug delivery system within the scope of our invention cancontain or comprise from about 5 μg to about 3 mg of an anti-neovascularagent, bevacizumab. Stated somewhat differently, drug delivery systemwithin the scope of our invention can release in vivo an average ofbetween about 10 ng to about 40 μg of an anti-neovascular agent (such asbevacizumab) over a 24 hour period after intraocular injection ofimplantation of the drug delivery system. Preferably, the drug deliverysystem releases an average of between about 14 μg to about 28 μg of theanti-neovascular agent (i.e. bevacizumab) over a 24 hour period afterintraocular injection of implantation of the drug delivery system. Morepreferably, the drug delivery system can release an average of betweenabout 7 μg to about 14 μg of the anti-neovascular agent (i.e.bevacizumab) over a 24 hour period after intraocular injection ofimplantation of the drug delivery system. In one embodiment the drugdelivery system can release between 10 ng and about 200 μg of ananti-neovascular agent (such as bevacizumab) over a 24 hour period afterintraocular injection of implantation of the drug delivery system.

A detailed method within the scope of our invention is a method fortreating dry AMD in a patient with dry AMD in one eye and wet AMD in theother eye, the method comprising the step of injecting a biocompatibledrug delivery system comprising an anti-neovascular agent and apolymeric vehicle associated with the anti-neovascular agent into thevitreous cavity of the dry AMD eye of the patient, thereby treating thedry AMD by preventing or by delaying the progression of the dry AMD towet AMD in the treated eye.

A further detailed method within the scope of our invention is a lowdose method for treating dry AMD, the method comprising the steps of:(a) preparing a biocompatible, sustained release drug delivery systemcomprising between about 5 μg and about 20 μg bevacizumab and apolymeric hyaluronic acid vehicle associated with the bevacizumab, (b)injecting the drug delivery system into the vitreous cavity of the eyeof a patient with dry AMD, and; (c) releasing from the drug deliverysystem an average of between about 14 nanograms to about 120 nanogramsof the bevacizumab over a 24 hour period over a period of time of about1 month or more, or for about 2 months or for about 3 months or more(preferably, the drug delivery system can release the active agent forbetween about 3 months and about 6 months), thereby treating the dry AMDwith low doses of the bevacizumab released from the drug deliverysystem. The other, non-injected eye of the patient can have wet AMD andthe dry AMD is treated by preventing or delaying onset of retinalneovascularization in the dry AMD eye injected.

The drug delivery system can have a viscosity of between about 130,000cps and about 300,000 cps at a shear rate of about 0.1/second at about25° C. and the drug delivery system can injected through a 25 to 30gauge syringe.

Our invention also encompasses a low dose method for treating dry AMD,the method comprising the steps of: (a) preparing a biocompatible,sustained release drug delivery system comprising between about 5 μg andabout 20 μg bevacizumab and a polymeric hyaluronic acid vehicleassociated with the bevacizumab, (b) using a 25 to 30 gauge syringeinjecting the drug delivery system into the vitreous cavity of the eyeof a patient with dry AMD, wherein the other, non-injected eye of thepatient has wet AMD, and; (c) releasing from the drug delivery system anaverage of between about 14 nanograms to about 120 nanograms of thebevacizumab over a 24 hour period over a period of time between about 3months and about 6 months, thereby treating the dry AMD with low dosesof the bevacizumab released from the drug delivery system by preventingor delaying onset of retinal neovascularization in the dry AMD eyeinjected, wherein the drug delivery system has a viscosity of betweenabout 130,000 cps and about 300,000 cps at a shear rate of about0.1/second at about 25° C.

A further method within the scope of our invention is a method forpreventing development of choroidal neovascularization, the methodcomprising the steps of: (a) preparing a biocompatible drug deliverysystem comprising an anti-neovascular drug and a polymeric hyaluronicacid associated with the anti-neovascular drug, and; (b) injecting thedrug delivery system into an intraocular location (such as a sub-tenon,subconjunctival, suprachoroidal, intrascleral, intravitreal orretrobulbar intraocular location) thereby preventing the development ofthe choroidal neovascularization. The polymeric hyaluronic acid used canbe a cross-linked hyaluronic acid or a noncross-linked hyaluronic acidor mixtures thereof and preferably, the polymeric hyaluronic acid has amolecular weight between about 1 million Daltons and about 2 millionDaltons.

To summarize, our invention encompasses compositions and method fortreating an ocular condition by preparing a biocompatible drug deliverysystem comprising a drug and a polymeric vehicle for the drug, andinjecting or implanting the drug delivery system into an intraocularlocation. The polymeric vehicle can be for example a collagen, apolysaccharide (such as a hydroxypropylmethylcellulose, alginate,chitosan, agar and pectin), a hyaluronic acid or a biodegradablepolymer, such as a PLGA or a PLA polymer. The intraocular location canbe an anterior or posterior intraocular location and the ocularcondition can be an anterior or posterior ocular condition. Theintraocular location can be a sub-tenon, subconjunctival,suprachoroidal, intrascleral, intravitreal or retrobulbar intraocularlocations.

DRAWING

FIG. 1 is a graph showing percent viability (Y axis) in vitro of theretinal pigment epithelial cells ARPE-19 (y-axis 100% viability is theviability of the ARPE-19 cells at time zero) after 24, 48 and 72 hourperiods of incubation in vitro in the concentrations of polysorbate 80shown on the X axis.

DESCRIPTION

Our invention is based upon the discovery that an anti-neovascular agentcan be used to treat a condition, such as dry AMD, even when noneovascularization is present in the dry AMD eye of the patient to betreated. Prior to our invention it was not known that ananti-neovascular agent could be used to treat a condition, such as dryAMD, where no neovascularization is present in the eye of the patient tobe treated. See eg Lin J., et al., Vascular Endothelial Growth FactorGene Polymorphisms in Age-related Macular Degeneration, Am J Ophthalmol.Mar. 29, 2008 (VEGF gene not associated with dry AMP patient DNA, and;Cook H., et al., Age-related macular degeneration: diagnosis andmanagement, Br Med Bull. 2008;85:127-49 (“ . . . there is no treatmentfor advanced dry AMD . . . ”). Our invention treats dry AMD bypreventing or by delaying progression of the dry AMD to wet AMD.

Without wishing to be bound by theory we can postulate a mechanism forthe effectiveness of our invention and embodiments therein. Thus, it canbe estimated that a patient with wet AMD in one eye has a 10% chance(each year) of developing neovascularization (wet AMD) in the other eye.These percentages are cummulative so that over 5 years the patient withone wet AMD in one eye has a 50% chance of developing wet AMD in theother eye, possibly due to the presence of mutation in the complementfactor H gene. We believe that genetically mediated processes which ledto development of wet AMD in one eye will over time prevail n the othereye, so that such patients are at high-risk for developing wet(neovascular) AMD in both eyes and preventative measures are thereforeindicated to reduce the chance of the patient developing severe visionloss in both eyes.

Hence, we postulate that anti-neovascular therapy can be effective totreat dry AMD, to thereby prevent it's progression to wet AMD, eventhough the dry AMD eye to be treated has little or noneovascularization. To reduce the chance of progressing from dry to wetAMD, relevant targets include the vascular endothelial growth factor(VEGF) pathway. VEGF is an important signaling protein involved in bothvasculogenesis and angiogenesis. In patients with dry AMD, anoverexpression of VEGF has been implicated in the progression to CNV.VEGF has been validated as an important target since VEGF-blockers, suchas Macugen™ (pegaptanib), a pegylated aptamer that specific blocksVEGF165, and more importantly, Avastin™ (bevacizumab), a monoclonalantibody which is more promiscuous and blocks all known VEGF isoformsVEGF121, VEGF165, VEGF189, and VEGF20. VEGF blockers have been usedextensively for CNV associated with AMD, proliferative diabeticretinopathy (PDR), neovascular glaucoma, diabetic macular edema (DME),and macular edema secondary to retinal vein occlusion (RVO). Resultswith anti-VEGF blockade are most impressive for CNV associated with AMD.

Although not currently approved by the FDA for such use, the injectionof 1.25 to 2.5 mg of aqueous (i.e. immediate release) bevacizumab (i.e.not as a sustained or extended release drug delivery system) into thevitreous cavity has been performed without significant intraoculartoxicity noted in both animal and human studies. The vitreous half-lifeof an anti-VEGF monoclonal antibody, such as bevacizumab, afterinjection into the vitreous from an immediate release (i.e. aqueous)formulation is only 5 to 6 days. Immediate release anti-neovascularformulations therefore cannot provide any ongoing or prolongedtherapeutic effect (due to the immediate, one-time release) and requirefrequent, painful re-injection to treat an ocular condition.

Thus, although intravitreal aqueous formulation bevacizumab doses ashigh as 1.25 to 2.5 mg have been administered to treat macularneovascularization (wet AMD) we believe it is possible that bevacizumabdoses less than 1% of known intravitreal dosages (i.e. less than 12 μg)can suppress neovascularization. We postulate that a dose of bevacizumabas low as 6.2 ug (i.e. as little as 0.5% of the known 1.25 mg dose) canbe used to treat or to prevent intraocular neovascularization in humans(i.e. to treat dry AMD). Thus, 1.25 mg to 2.5 mg of an anti-neovascularagent, such as bevacizumab, can be released into the vitreous over a3-6-month period from a sustained release drug delivery system toprovide long term treatment of a chronic ocular condition such as dryAMD.

A hydrogel is a colloidal gel formed as a dispersion in water or otheraqueous medium. Thus a hydrogel is formed upon formation of a colloid inwhich a dispersed phase (the polymer) has combined with a continuousphase (i.e. water) to produce a viscous jellylike product; for example,coagulated silicic acid. A hydrogel is a three-dimensional network ofhydrophilic polymer chains that are crosslinked through either chemicalor physical bonding. Because of the hydrophilic nature of the polymerchains, hydrogels absorb water and swell (unless they have alreadyabsorbed their maximum amount of water). The swelling process is thesame as the dissolution of non-crosslinked hydrophilic polymers. Bydefinition, water constitutes at least 10% of the total weight (orvolume) of a hydrogel.

Examples of hydrogels include synthetic polymers such as polyhydroxyethyl methacrylate, and chemically or physically crosslinked polyvinylalcohol, polyacrylamide, poly(N-vinyl pyrolidone), polyethylene oxide,and hydrolysed polyacrylonitrile. Examples of hydrogels which areorganic polymers include covalent or ionically crosslinkedpolysaccharide-based hydrogels such as the polyvalent metal salts ofalginate, pectin, carboxymethyl cellulose, heparin, hyaluronate andhydrogels from chitin, chitosan, pullulan, gellan and xanthan. Theparticular hydrogels used in our experiment were a cellulose compound(i.e. hydroxypropylmethylcellulose [HPMC]) and a high molecular weighthyaluronic acid (HA).

As an embodiment of our invention we made a hydrogel formulation forintravitreal injection using a polymeric hyaluronic acid and ananti-VEGF monoclonal antibody. This drug delivery system can providesustained-release of a low daily dose of the anti-VEGF monoclonalantibody over a 3 to 6 month period and prevent of conversion from dryto wet AMD. The drug delivery system can also comprise microsphereencapsulation of the anti-VEGF antibody in the hydrogel. Thesustained-release drug delivery system can provide the necessaryanti-VEGF blockade in eye to reduce the chance of progression from dryto neovascular AMD. In addition, the low doses released in the eye overa prolonged period of time do not provide a systemic toxic level of theanti-neovascular agent.

Our sustained release drug delivery system can also be used to providesustained-release anti-VEGF blockade in patients with central retinalvein occlusion that are at risk for neovascularization and in patientswith severe non-proliferative diabetic retinopathy that are at risk ofprogressing to neovascular disease.

Alternately, the drug delivery system can be a PLGA implant, liposomalencapsulated antibodies optionally entrapped in a cross-linkedhyaluronic acid. Additionally, microspheres, microcapsules (ranging from0.001 to 100 microns) and liposomes with modified surfaces to create aninteraction with the hydrogel polymer to modify release. Other anti-VEGFcompounds can be used in place of an anti-VEGF monoclonal antibody (e.g.bevacizumab)and these include anti-VEGF aptamers (e.g. pegaptanib),soluble recombinant decoy receptors (e.g. VEGF Trap), antibody fragments(e.g. ranibizumab), corticosteroids, small interfering RNA's decreasingexpression of VEGFR or VEGF ligand, post-VEGFR blockade with tyrosinekinase inhibitors, MMP inhibitors, IGFBP3, SDF-1 blockers, PEDF,gamma-secretase, Delta-like ligand 4, integrin antagonists, HIF-1 alphablockade, protein kinase CK2 blockade, and inhibition of stem cell (i.e.endothelial progenitor cell) homing to the site of neovascularizationusing vascular endothelial cadherin (CD-144) and stromal derived factor(SDF)-1 antibodies. Agents that have activity against CNV that are notnecessarily anti-VEGF compounds can also be used and includeanti-inflammatory drugs, rapamycin, cyclosporine, anti-TNF agents, andanti-complement agents.

Our invention also encompasses particular drug delivery systemformulations and methods for administering these drug delivery systemsfor treating an ocular condition, such as dry AMD. The present inventionencompasses drug delivery systems which are structured and configuredsolely for intraocular, as opposed to topical or systemic,administration. The intraocular administration can be by implantation orinjection into the vitreous cavity (posterior chamber) of the eye. Thedrug delivery systems within the scope of our invention can bebiodegradable implants and/or microspheres. The drug delivery systemscan be monolithic, that is the active agent is homogenously distributedor dispersed throughout the biodegradable polymer. The therapeutic agentcan be released from drug delivery systems made according to the presentinvention for a period of time between about 2 hours to 12 months ormore. An important feature of our drug delivery systems is that they donot include any means (such as a cap, protrusion or suture tab) forfixing the drug delivery system to the intraocular location to which itis administered.

An important characteristic of a drug delivery system within the scopeof our invention is that it can be implanted or injected into anintraocular location (such as an anterior sub-Tenon, subconjunctival,intravitreal or suprachoroidal location) to provide sustained release ofa therapeutic agent without the occurrence of or the persistence ofsignificant immunogenicity at and adjacent to the site of theintraocular implantation or injection.

Polylactide (PLA) polymers exist in 2 chemical forms, poly(L-lactide)and poly(D,L-lactide). The pure poly(L-lactide) is regioregular andtherefore is also highly crystalline, therefore degrades in vivo at avery slow rate. The poly(D,L-lactide) is regiorandom which leads to morerapid degradation in vivo. Therefore a PLA polymer which is a mixture ofpredominantly poly(L-lactide) polymer, the remainder being apoly(D-lactide) polymer will degrade in vivo at a rate slower that a PLApolymer which is predominantly poly(D-lactide) polymer. A PLGA is aco-polymer that combines poly(D,L-lactide) with poly(glycolide) invarious possible ratios. The higher the glycolide content in a PLGA thefaster the polymer degradation.

In one embodiment of our invention, a drug delivery system forintraocular administration (i.e. by intravitreal implantation orinjection) comprises configured, consists of, or consists essentially ofat least a 75 weight percent of a PLA and no more than about a 25 weightpercent of a poly(D,L-lactide -co-glycolide) polymer.

Within the scope of our invention are suspensions of microspheres(incorporating an anti-neovascular agent) suspended in a hydrogel (suchas a polymeric hyaluronic acid) which can be administered to anintraocular location through a syringe needle. Administration of such asuspension requires that the viscosity of the microsphere suspension at25° C. be less than about 300,000 cP. The viscosity of water at 25° C.is about 1. cP (cP or cps is centiposie, a measure of viscosity). At 25°C. the viscosity of olive oil is 84 cP, of castor oil 986 P and ofglycerol 1490 cP

The drug delivery systems of our invention can include a therapeuticagent mixed with or dispersed within a biodegradable polymer. The drugdelivery systems compositions can vary according to the preferred drugrelease profile, the particular active agent used, the ocular conditionbeing treated, and the medical history of the patient. Therapeuticagents which can be used in our drug delivery systems include, but arenot limited to (either by itself in a drug delivery system within thescope of the present invention or in combination with anothertherapeutic agent): ace-inhibitors, endogenous cytokines, agents thatinfluence basement membrane, agents that influence the growth ofendothelial cells, adrenergic agonists or blockers, cholinergic agonistsor blockers, aldose reductase inhibitors, analgesics, anesthetics,antiallergics, anti-inflammatory agents, antihypertensives, pressors,antibacterials, antivirals, antifungals, antiprotozoals,anti-infectives, antitumor agents, antimetabolites, antiangiogenicagents, tyrosine kinase inhibitors, antibiotics such as aminoglycosidessuch as gentamycin, kanamycin, neomycin, and vancomycin; amphenicolssuch as chloramphenicol; cephalosporins, such as cefazolin HCl;penicillins such as ampicillin, penicillin, carbenicillin, oxycillin,methicillin; lincosamides such as lincomycin; polypeptide antibioticssuch as polymixin and bacitracin; tetracyclines such as tetracycline;quinolones such as ciproflaxin, etc.; sulfonamides such as chloramine T;and sulfones such as sulfanilic acid as the hydrophilic entity,anti-viral drugs, e.g. acyclovir, gancyclovir, vidarabine,azidothymidine, azathioprine, dideoxyinosine, dideoxycytosine,dexamethasone, ciproflaxin, water soluble antibiotics, such asacyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine,dideoxycytosine; epinephrine; isoflurphate; adriamycin; bleomycin;mitomycin; ara-C; actinomycin D; scopolamine; and the like, analgesics,such as codeine, morphine, keterolac, naproxen, etc., an anesthetic,e.g. lidocaine; beta.-adrenergic blocker or beta.-adrenergic agonist,e.g. ephidrine, epinephrine, etc.; aldose reductase inhibitor, e.g.epairestat, ponalrestat, sorbinil, tolrestat; antiallergic, e.g.cromolyn, beclomethasone, dexamethasone, and flunisolide; colchicine,anihelminthic agents, e.g. ivermectin and suramin sodium; antiamebicagents, e.g. chloroquine and chlortetracycline; and antifungal agents,e.g. amphotericin, etc., anti-angiogenesis compounds such as anecortaveacetate, retinoids such as Tazarotene, anti-glaucoma agents, such asbrimonidine (Alphagan and Alphagan P), acetozolamide, bimatoprost(Lumigan), timolol, mebefunolol; memantine, latanoprost (Xalatan);alpha-2 adrenergic receptor agonists; 2-methoxyestradiol;anti-neoplastics, such as vinblastine, vincristine, interferons; alpha,beta and gamma, antimetabolites, such as folic acid analogs, purineanalogs, and pyrimidine analogs; immunosuppressants such as azathiprine,cyclosporine and mizoribine; miotic agents, such as carbachol, mydriaticagents such as atropine, protease inhibitors such as aprotinin,camostat, gabexate, vasodilators such as bradykinin, and various growthfactors, such epidermal growth factor, basic fibroblast growth factor,nerve growth factors, carbonic anhydrase inhibitors, and the like.

In particular embodiments of our invention, the active agent can be acompound that blocks or reduces the expression of VEGF receptors (VEGFR)or VEGF ligand including but not limited to anti-VEGF aptamers (e.g.Pegaptanib), soluble recombinant decoy receptors (e.g. VEGF Trap),anti-VEGF monoclonal antibodies (e.g. Bevacizamab) and/or antibodyfragments (e.g. Ranibizamab), small interfering RNA's decreasingexpression of VEGFR or VEGF ligand, post-VEGFR blockade with tyrosinekinase inhibitors, MMP inhibitors, IGFBP3, SDF-1 blockers, PEDF,gamma-secretase, Delta-like ligand 4, integrin antagonists, HIF-1 alphablockade, protein kinase CK2 blockade, and inhibition of stem cell (i.e.endothelial progenitor cell) homing to the site of neovascularizationusing vascular endothelial cadherin (CD-144) and stromal derived factor(SDF)-1 antibodies.

In another embodiment or variation of our invention the active agent ismethotrexate. In another variation, the active agent is a retinoic acid.In another variation, the active agent is an anti-inflammatory agentsuch as a nonsteroidal anti-inflammatory agent. Nonsteroidalanti-inflammatory agents that may be used include, but are not limitedto, aspirin, diclofenac, flurbiprofen, ibuprofen, ketorolac, naproxen,and suprofen. In a further variation, the anti-inflammatory agent is asteroidal anti-inflammatory agent, such as dexamethasone.

Steroidal anti-inflammatory agents that can be used in our drug deliverysystems can include, but are not limited to, 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide, and any of their derivatives.

In one embodiment, cortisone, dexamethasone, fluocinolone,hydrocortisone, methylprednisolone, prednisolone, prednisone, andtriamcinolone, and their derivatives, are preferred steroidalanti-inflammatory agents. In another preferred variation, the steroidalanti-inflammatory agent is dexamethasone. In another variation, thebiodegradable implant includes a combination of two or more steroidalanti-inflammatory agents.

The active agent, such as an anti-neovascular agent, can comprise fromabout 1% to about 90% by weight of the implant or drug delivery system.In one variation, the agent is from about 5% to about 80% by weight ofthe implant. In a preferred variation, the agent comprises from about10% to about 60% by weight of the implant. In a more preferredembodiment of the present invention, the agent can comprise about 50% byweight of the implant.

The therapeutic active agent present in our drug delivery systems can behomogeneously dispersed in the biodegradable polymer of the drugdelivery system. The selection of the biodegradable polymer used canvary with the desired release kinetics, patient tolerance, the nature ofthe disease to be treated, and the like. Polymer characteristics thatare considered include, but are not limited to, the biocompatibility andbiodegradability at the site of implantation, compatibility with theactive agent of interest, and processing temperatures. The biodegradablepolymer matrix usually comprises at least about 10, at least about 20,at least about 30, at least about 40, at least about 50, at least about60, at least about 70, at least about 80, or at least about 90 weightpercent of the implant. In one variation, the biodegradable polymermatrix comprises about 40% to 50% by weight of the drug delivery system.

Biodegradable polymers which can be used include, but are not limitedto, polymers made of monomers such as organic esters or ethers, whichwhen degraded result in physiologically acceptable degradation products.Anhydrides, amides, orthoesters, or the like, by themselves or incombination with other monomers, may also be used. The polymers aregenerally condensation polymers. The polymers can be crosslinked ornon-crosslinked.

For the most part, besides carbon and hydrogen, the polymers willinclude oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen can be present as amide, cyano, and amino. An exemplary list ofbiodegradable polymers that can be used are described in Heller,Biodegradable Polymers in Controlled Drug Delivery, In: “CRC CriticalReviews in Therapeutic Drug Carrier Systems”, Vol. 1. CRC Press, BocaRaton, Fla. (1987).

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are homo- or copolymers of D-lactic acid,L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, andcombinations thereof. Copolymers of glycolic and lactic acid are ofparticular interest, where the rate of biodegradation is controlled bythe ratio of glycolic to lactic acid. The percent of each monomer inpoly(lactic-co-glycolic)acid (PLGA) copolymer may be 0-100%, about15-85%, about 25-75%, or about 35-65%. In certain variations, 25/75 PLGAand/or 50/50 PLGA copolymers are used. In other variations, PLGAcopolymers are used in conjunction with polylactide polymers.

Other agents may be employed in a drug delivery system formulation for avariety of purposes. For example, buffering agents and preservatives maybe employed. Preservatives which may be used include, but are notlimited to, sodium bisulfite, sodium bisulfate, sodium thiosulfate,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuricacetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol andphenylethyl alcohol. Examples of buffering agents that may be employedinclude, but are not limited to, sodium carbonate, sodium borate, sodiumphosphate, sodium acetate, sodium bicarbonate, and the like, as approvedby the FDA for the desired route of administration. Surfactants whichcan be used to stabilize particles in a colloid and/or electrolytes suchas sodium chloride and potassium chloride can also be included in theformulation. The drug delivery system can also acid and basic excipientsto control pH in the microenvironment as well as at interfaces(diffusional stagnant layer).

The biodegradable drug delivery systems can also include additionalhydrophilic or hydrophobic compounds that accelerate or retard releaseof the active agent. Additionally, release modulators such as thosedescribed in U.S. Pat. No. 5,869,079 can be included in the implants.The amount of release modulator employed will be dependent on thedesired release profile, the activity of the modulator, and on therelease profile of the glucocorticoid in the absence of modulator. Wherethe buffering agent or release enhancer or modulator is hydrophilic, itmay also act as a release accelerator. Hydrophilic additives act toincrease the release rates through faster dissolution of the materialsurrounding the drug particles, which increases the surface area of thedrug exposed, thereby increasing the rate of drug diffusion. Similarly,a hydrophobic buffering agent or enhancer or modulator can dissolve moreslowly, slowing the exposure of drug particles, and thereby slowing therate of drug diffusion.

A drug delivery system within the scope of the present invention can beformulated with particles of an active agent dispersed within abiodegradable polymer. Without being bound by theory, it is believedthat the release of the active agent can be achieved by erosion of thebiodegradable polymer matrix and by diffusion of the particulate agentinto an ocular fluid, e.g., the vitreous, with subsequent dissolution ofthe polymer matrix and release of the active agent. Factors whichinfluence the release kinetics of active agent from the implant caninclude such characteristics as the size and shape of the implant, thesize of the active agent particles, the solubility of the active agent,the ratio of active agent to polymer(s), the method of manufacture, thesurface area exposed, the density of the implant and the erosion rate ofthe polymer(s).

The release rate of the active agent can depend at least in part on therate of degradation of the polymer backbone component or componentsmaking up the biodegradable polymer matrix. For example, condensationpolymers may be degraded by hydrolysis (among other mechanisms) andtherefore any change in the composition of the implant that enhanceswater uptake by the implant will likely increase the rate of hydrolysis,thereby increasing the rate of polymer degradation and erosion, and thusincreasing the rate of active agent release. The release rate of theactive agent can also be influenced by the crystallinity of the activeagent, the pH in the implant and the pH at interfaces.

The release kinetics of the drug delivery systems of the presentinvention can be dependent in part on the surface area of the drugdelivery systems. A larger surface area exposes more polymer and activeagent to ocular fluid, causing faster erosion of the polymer anddissolution of the active agent particles in the fluid.

Examples of ocular conditions which can be treated by the drug deliverysystems and methods of the invention include, but are not limited to,glaucoma, uveitis, macular edema, macular degeneration, retinaldetachment, posterior ocular tumors, fungal or viral infections,multifocal choroiditis, diabetic retinopathy, proliferativevitreoretinopathy (PVR), sympathetic opthalmia, Vogt Koyanagi-Harada(VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion.In one variation, the implants are particularly useful in treating suchmedical conditions as uveitis, macular edema, vascular occlusiveconditions, proliferative vitreoretinopathy (PVR), and various otherretinopathies.

The drug delivery systems of our invention can be injected to anintraocular location by syringe or can be inserted (implanted) into theeye by a variety of methods, including placement by forceps, by trocar,or by other types of applicators, after making an incision in thesclera. In some instances, a trocar or applicator may be used withoutcreating an incision. In a preferred variation, a hand held applicatoris used to insert one or more biodegradable implants into the eye. Thehand held applicator typically comprises an 18-30 GA stainless steelneedle, a lever, an actuator, and a plunger. Suitable devices forinserting an implant or implants into a posterior ocular region or siteincludes those disclosed in U.S. patent application Ser. No. 10/666,872.

The method of administration generally first involves accessing thetarget area within the ocular region with the needle, trocar orimplantation device. Once within the target area, e.g., the vitreouscavity, a lever on a hand held device can be depressed to cause anactuator to drive a plunger forward. As the plunger moves forward, itcan push the implant or implants into the target area (i.e. thevitreous).

Various techniques may be employed to make implants within the scope ofthe present invention. Useful techniques include phase separationmethods, interfacial methods, extrusion methods, compression methods,molding methods, injection molding methods, heat press methods and thelike.

The drug delivery systems disclosed herein can be used to prevent or totreat various ocular diseases or conditions, including the following:maculopathies/retinal degeneration: macular degeneration, including agerelated macular degeneration (ARMD), such as non-exudative age relatedmacular degeneration and exudative age related macular degeneration,choroidal neovascularization, retinopathy, including diabeticretinopathy, acute and chronic macular neuroretinopathy, central serouschorioretinopathy, and macular edema, including cystoid macular edema,and diabetic macular edema. Uveitis/retinitis/choroiditis: acutemultifocal placoid pigment epitheliopathy, Behcet's disease, birdshotretinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), uveitis, including intermediate uveitis (pars planitis)and anterior uveitis, multifocal choroiditis, multiple evanescent whitedot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis,serpignous choroiditis, subretinal fibrosis, uveitis syndrome, andVogt-Koyanagi-Harada syndrome. Vascular diseases/exudative diseases:retinal arterial occlusive disease, central retinal vein occlusion,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, Eales disease.Traumatic/surgical: sympathetic ophthalmia, uveitic retinal disease,retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusionduring surgery, radiation retinopathy, bone marrow transplantretinopathy. Proliferative disorders: proliferative vitreal retinopathyand epiretinal membranes, proliferative diabetic retinopathy. Infectiousdisorders: ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associatedwith HIV infection, uveitic disease associated with HIV Infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis. Genetic disorders:retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Bests disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, pseudoxanthoma elasticum. Retinal tears/holes:retinal detachment, macular hole, giant retinal tear. Tumors: retinaldisease associated with tumors, congenital hypertrophy of the RPE,posterior uveal melanoma, choroidal hemangioma, choroidal osteoma,choroidal metastasis, combined hamartoma of the retina and retinalpigmented epithelium, retinoblastoma, vasoproliferative tumors of theocular fundus, retinal astrocytoma, intraocular lymphoid tumors.Miscellaneous: punctate inner choroidopathy, acute posterior multifocalplacoid pigment epitheliopathy, myopic retinal degeneration, acuteretinal pigment epithelitis and the like.

EXAMPLES

The following examples illustrate aspects and embodiments of ourinvention.

Example 1 Intravitreal Bevacizumab-PLGA Microspheres for Treatment ofDry AMD

A 78 year old man has age-related macular degeneration and cataracts inboth eyes. The patient can also have a history of cardiovascular diseaseand an inferior wall myocardial infarction 6 months previous. Thepatient can complain of blurry vision and metamorphopsia in the righteye and examination can reveal visual acuity of 20/400 right eye, 20/32left eye. Retinal examination can show subfoveal choroidalneovascularization (CNV) (right eye wet AMD) approximately 1 disc areain size with surrounding hemorrhage and edema in the right eye. Thefellow left eye can show high-risk features for developing wet AMD suchas soft, amorphic appearing drusen that included the fovea but no signsof choroidal neovascularization and can be confirmed by fluoresceinangiography (left eye dry AMD). The patient can be started on monthlyintravitreal injections of ranibizumab (an anti-neovascular agent) inthe right wet AMD eye with resolution of the edema and hemorrhage and areturn in visual acuity to 20/125 within 4 months.

In the left eye, the patient can receive an intravitreal injection of asustained-release anti-VEGF monoclonal antibody formulation (optionallywith a penetration enhancer) to prophylax against development of CNV inthis eye given that he is now at high risk for developing wet AMD in thebetter seeing left eye. The injected volume can be 50 ul comprisingbevacizumab incorporated into PLGA microspheres with a total bevacizumab(drug) weight of 2.5 mg.

Polysorbate 20 PLGA microspheres with an in vitro release rate of 10ug/day can also be placed in the formulation to enhance retinalpermeability. The bevacizumab and polysorbate 20 microspheres are placedin a cross-linked hyaluronic acid at a concentration of 1.2% withreasonable syringability using a 27 G needle.

The patient can receive the intravitreal left eye injections of the 50ul of bevacizumab-PLGA microspheres (total drug weight 2.5 mg) inventionevery 6 months and at the end of a 7-year follow up period the patientcan have maintained vision in the left eye at 20/32. His risk of havingdeveloped wet AMD in this left eye was over 50% but repeat examinationcan reveal no signs of CNV in the left eye. Unfortunately, at the end ofthe 7 year follow up, the vision in the right eye can have deterioratedto 20/400 with an organized disciform scar present on examination in thecentral macular area. Given that he does not lose vision in the lefteye, he is able to maintain a driver's license and an independent lifestyle over this time frame. Despite have been exposed to sustained-lowdose anti-VEGF therapy in the eye, the patient's cardiovascular diseasecan remain unchanged without experience of any thromboembolic events.

The microspheres used therapeutically in Examples 1 to 3 can be made bya solvent evaporation method from methylene chloride into a PVA(polyvinyl alcohol) solution. From 10 to 100 mg/mL of the microspherescan be suspended in an isotonic phosphate buffer solution and from 50 to200 μL of the microsphere suspension can be administered to anintraocular location.

The anti-neovascular agent microspheres with the anti-neovascular agenthomogenously distributed or dispersed throughout the selected polylacticacid (PLA) or PLGA resin can be manufactured using an emulsion/solventevaporation technique. The non-solvent (continuous aqueous phase) issaturated with the anti-neovascular agent to prevent loss of theanti-neovascular agent from the polymer phase and increase loadingefficiency. Additionally, the anti-neovascular agent saturated withmethanol can be used to quench the emulsion. The methanol served as asink to remove the dichloromethane quickly, hardening the microspheresbefore the anti-neovascular agent can diffuse out of them.

Example 2 Low Dose Intravitreal Bevacizumab-PLGA Microspheres forTreatment of Dry AMD

A 74 year old man is diagnosed with dry age-AMD in one (right) eye andwet AMD in the other (left) eye. He has 20/40 vision in his right eye.He is treated by intravitreal injection into the dry AMD eye of asustained release drug delivery system. Sustained release drug deliverysystem comprises a total of about 6 micrograms (low dose) of the activeagent bevacizumab in a polymeric vehicle. The polymeric vehicle is ahigh viscosity hyaluronic acid or a PLGA or PLA associated with thebevacizumab anti-neovascular agent to form either a plurality ofmicrospheres or a single monolithic implant in which the bevacizumab ishomogenously distributed. Alternately the sustained release drugdelivery system can comprise the bevacizumab microspheres or implant inthe hyaluronic acid (cross-linked or non-cross linked), so that both aviscous (the hyaluronic acid) and the solid (the PLA or PLGAmicrospheres or implant) polymeric vehicles are present in the same drugdelivery system. The drug delivery system can release the 6 μg ofbevacizumab into the vitreous over a 1 to 6 month period, after whichthe patient's right eye can show no evidence of neovascularization andthe same vision maintained (20/40) in his right eye.

Example 3 Intravitreal Ranibizumab-PLGA Microspheres for Treatment ofDry AMD

An 83 year old woman can wake up with blurry vision in the left eye. Shecan have a history of glaucoma, s/p cataract removal with IOLs(intraocular lenses), and dry AMD in both eyes and can be takingAlphagan P eye drops. The patient's ophthalmologist can examine her andshe can be diagnosed with left eye wet AMD and sent immediately to aretinal specialist. The vision can be 20/25 in the right eye and 20/200in the left eye. Retinal examination can show dry changes in the righteye macula but high risk features such as large drusen and numerouspigmentary changes in the subfoveal region. The left eye macula can showa subfoveal CNV approximately 2 disc areas in size with surroundingmacular edema and intraretinal hemorrhages. Fluorescein angiography canconfirm the presence of left eye CNV predominantly classic inappearance. The patient can be immediately started on monthlyintravitreal injections of ranibizumab in the wet AMD left eye withresolution of the retinal edema over a 3 month period but she canexperience only a modest improvement of left eye visual acuity to20/100. Since the patient was at high risk for developing CNV in herright eye, and the vision in the left eye may not appreciably improveover the 3 month period, she can receive an intravitreal injection intothe right eye of 50 ul comprising 4.8 mg of ranibizumab incorporatedinto PLGA microspheres, to prophylax against the development of CNV inthe right eye. Polysorbate 20 PLGA microspheres with an in vitro releaserate of 5 ug/day can also be placed in the formulation to enhanceretinal permeability. The microspheres can be placed in a partiallycross-linked hyaluronic acid (HA) at a HA concentration of 2.1%. Such across-linked HA can be obtained from Allergan Medical (Irvine, Calif.)under the brand names Juvederm Ultra Plus, Juvederm 30, Captique, andVoluma.

She can have repeat right eye intravitreal injections of the 50 ulcomprising 4.8 mg of ranibizumab-PLGA microspheres every 6 months over a4 year period with visual acuity remaining 20/25 in the right eye and20/200 for the left eye. Retinal examination can show dry AMD in theright eye and an organized disciform scar in the left eye with mildsubfoveal fibrosis. She can be able to live independently in her ownhome given the excellent vision that she can maintain in her right eye.

Example 4 Anti-Neovascular Drug Delivery System with a RetinalPenetration Enhancer

An experiment was carried out to examine the toxicity of a polysorbateretinal penetrant enhancer to retinal pigment epithelial (“RPE”) cells.Thus, ARPE-19 cells (see Dunn K. et al., ARPE-19, a human retinalpigment epithelial cell line with differentiated properties, Exp EyeRes. February 1992;62(2):155-69) were incubated in vitro inconcentrations of polysorbate 80 ranging from 0% to 0.10% w/w and a cellviability assay was performed.

The protocol for this in vitro experiment was as follows: ARPE-19 cells(passage 11 to 23) were seeded the day prior to experimentation in 24well-plates at 125.000 cells/well in DMEM:F12 medium supplemented with10% FBS. Time course and dose response were simultaneously performed onARPE-19 cells. Parameters of incubating solutions such as pH, osmolaritywere measured for every concentration. Times of incubation were 24 h, 48h, 72 h. One negative (non-treated) and one positive control (5 mM H₂O₂)were included. Non-treated condition was cell culture mediumsupplemented with serum. 5 mM H₂O₂ was prepared from 3% H₂O₂ stocksolution (875 mM). Concentrations applied to cells were determinedconsidering several parameters, such as:

-   (a) commonly used concentration in formulation.-   (b) limiting concentration to compound solubility.-   (c) limiting concentration to applicable viscosity, osmolarity and    pH values.    In a first approach, the concentrations covered a wide range (Exp.    1). After preliminary results, a second set of experiments (Exp. 2    to 4) determined more accurately compound concentrations leading to    inhibition of 50% of cell viability, based on cell viability assay    and morphological aspect. All range of concentrations were obtained    with serial dilution from most the concentrated condition into cell    culture medium (DMEM:F12 supplemented with 10% FBS). Results from    MTT assay were expressed as a percentage of cell viability    calculated as follows:

% cell viability=ODtest/ODcontrol×100.

After 3 experiments were independently completed in the same conditions,a graph was plotted from 3 sets of values, yielding tointer-experimental standard variation values. Gap concentration bringingto 50% cell viability was therefore determined. Morphological appearancewas analyzed by semi-quantitative scoring ranging from 5 to 1, fromnormal to lethal phenotype respectively.

It was observed that polysorbate 80 concentrations over about 0.06% (0.6mg/ml) were associated with declining RPE cell viability, andpolysorbate 80 concentrations greater than about approximately 0.09%(0.9 mg/ml) were associated with cell viabilities of less than 50%, asshown by FIG. 1. Assuming a vitreous volume of 4 ml in a human eye, thetotal maximum weight of polysorbate in the vitreous at one timetherefore should not exceed 3.6 mg.

In each of Examples 1-3 above one or more retinal penetration enhancerscan be included in the drug delivery system to increase the permeabilityof the retina to the anti-neovascular agent used. Thus, a retinalpenetration enhancers can be added to the sustained release drugdelivery system to release concomitantly with the anti-neovascular agent(i.e. an anti-VEGF compound). Co-releasing both a low dose of anti-VEGFcompound and a penetration enhancer over a 6 month period can optimizethe efficiency of the anti-VEGF compounds especially the larger onessuch as a monoclonal antibody, to reach the sub-retinal space to treatCNV. A preferred retinal penetrant enhancer is polysorbate 20 (eg Tween20 or C12-sorbitan-E20) and polysorbate 80, added to the drug deliverysystem as an aqueous solution with a concentration of the retinalpenetration enhancer in the aqueous solution of between about from0.005% to 0.10% (0.05 mg to 1 mg of the retinal penetration enhancer perml water. Alternative retinal penetration enhancers include but are notlimited to sodium laurylsulfate, benzalkonium chloride, andcyclodextrans.

All references, articles, patents, applications and publications setforth above are incorporated herein by reference in their entireties.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

1. A method for treating dry age related macular degeneration (“dry AMD”), the method comprising the step of administering an anti-neovascular agent to an eye of a patient with dry AMD, thereby treating the dry AMD.
 2. The method of claim 1, wherein the anti-neovascular agent is an anti-vascular endothelial growth factor (“anti-VEGF”) agent.
 3. The method of claim 2, wherein the anti-VEGF agent is selected from the group consisting of bevacizumab, ranibizumab and pegaptanib and derivatives, esters, salts and mixtures thereof.
 4. The method of claim 1, wherein the anti-neovascular agent is administered as a biocompatible drug delivery system.
 5. The method of claim 4, wherein the biocompatible drug delivery system comprises the anti-neovascular agent and a polymeric vehicle associated with the anti-neovascular agent.
 6. The method of claim 5, wherein the polymeric vehicle is selected from the group consisting of a polymeric lactic acid, a polymeric glycolic acid, a lactic acid-glycolic acid co-polymer (“PLGA”), a polymeric hydroxypropylmethylcellulose, and a polymeric hyaluronic acid, and mixtures thereof.
 7. The method of claim 5, wherein the anti-neovascular agent is associated with the polymeric vehicle by being dispersed homogenously throughout the polymeric vehicle.
 8. The method of claim 1, wherein the administering step is carried out by injecting the anti-neovascular agent to an anterior intraocular location.
 9. The method of claim 1, wherein the administering step is carried out by injecting the anti-neovascular agent to a posterior intraocular location.
 10. The method of claim 9, wherein the administering step is carried out by injecting the anti-neovascular agent into the vitreous cavity.
 11. A method for treating dry AMD, the method comprising the steps of: (a) preparing a biocompatible drug delivery system comprising an anti-neovascular agent and a polymeric vehicle associated with the anti-neovascular agent, and; (b) injecting the drug delivery system into the vitreous cavity of the eye of a patient with dry AMD, thereby treating the dry AMD.
 12. The method of claim 11, wherein the anti-neovascular agent is bevacizumab or a derivative, ester, or salt thereof.
 13. The method of claim 12, wherein the drug delivery system comprises from about 5 μg to about 3 mg bevacizumab.
 14. The method of claim 13, wherein the polymeric vehicle is selected from the group consisting of a polymeric lactic acid, a polymeric glycolic acid, a PLGA, a polymeric hydroxypropylmethylcellulose, and a polymeric hyaluronic acid, and mixtures thereof. acid and mixtures thereof.
 15. The method of claim 14, wherein the drug delivery system releases an average of between about 10 ng to about 40 μg of the bevacizumab over a 24 hour period.
 16. The method of claim 15, wherein the drug delivery system releases an average of between about 14 μg to about 28 μg of the bevacizumab over a 24 hour period.
 17. The method of claim 16, wherein the drug delivery system releases an average of between about 7 μg to about 14 μg of the bevacizumab over a 24 hour period.
 18. A method for treating dry AMD in a patient with dry AMD in one eye and wet AMD in the other eye, the method comprising the step of injecting a biocompatible drug delivery system comprising an anti-neovascular agent and a polymeric vehicle associated with the anti-neovascular agent into the vitreous cavity of the dry AMD eye of the patient, thereby treating the dry AMD.
 19. The method of claim 18, wherein the dry AMD is treated by preventing or by delaying the progression of the dry AMD to wet AMD in the treated eye.
 20. A low dose method for treating dry AMD, the method comprising the steps of: (a) preparing a biocompatible, sustained release drug delivery system comprising between about 5 μg and about 20 μg bevacizumab and a polymeric hyaluronic acid vehicle associated with the bevacizumab; (b) injecting the drug delivery system into the vitreous cavity of the eye of a patient with dry AMD, and; (c) releasing from the drug delivery system an average of between about 14 nanograms to about 120 nanograms of the bevacizumab over a 24 hour period over a period of time between about 3 months and about 6 months, thereby treating the dry AMD with low doses of the bevacizumab released from the drug delivery system.
 21. The method of claim 21, wherein the other, non-injected eye of the patient has wet AMD.
 22. The method of claim 21, wherein the dry AMD is treated by preventing or delaying onset of retinal neovascularization in the dry AMD eye injected.
 23. The method of claim 21, wherein the drug delivery system a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C.
 24. The method of claim 21, wherein the drug delivery system is injected using a 25 to 30 gauge syringe.
 25. A low dose method for treating dry AMD, the method comprising the steps of: (a) preparing a biocompatible, sustained release drug delivery system comprising between about 5 μg and about 20 μg bevacizumab and a polymeric hyaluronic acid vehicle associated with the bevacizumab, (b) using a 25 to 30 gauge syringe injecting the drug delivery system into the vitreous cavity of the eye of a patient with dry AMD, wherein the other, non-injected eye of the patient has wet AMD, and; (c) releasing from the drug delivery system an average of between about 14 nanograms to about 120 nanograms of the bevacizumab over a 24 hour period over a period of time between about 3 months and about 6 months, thereby treating the dry AMD with low doses of the bevacizumab released from the drug delivery system by preventing or delaying onset of retinal neovascularization in the dry AMD eye injected, wherein the drug delivery system has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C.
 26. A method for preventing development of ocular neovascularization, the method comprising the steps of: (a) preparing a biocompatible drug delivery system comprising an anti-neovascular drug and a polymeric hyaluronic acid associated with the anti-neovascular drug, and; (b) injecting the drug delivery system into an intraocular location of a patient's eye, thereby preventing the development of the choroidal neovascularization.
 27. The method of claim 26 wherein the polymeric hyaluronic acid is a cross-linked hyaluronic acid.
 28. The method of claim 26 wherein the polymeric hyaluronic acid is a noncross-linked hyaluronic acid.
 29. The method of claim 26 wherein the polymeric hyaluronic acid has a molecular weight between about 1 million Daltons and about 2 million Daltons.
 30. The method of claim 26, wherein the intraocular location is selected from the group of intraocular locations consisting of sub-tenon, subconjunctival, suprachoroidal, intrascleral, intravitreal and retrobulbar intraocular locations.
 31. The method of claim 26, wherein the patient has an ocular condition selected from the ocular conditions dry AMD, central retinal vein occlusion without neovascularization and non-proliferative diabetic retinopathy. 